We propose to continue a longitudinal study of 717 pairs of female twins from two population-based cohorts with the aim of understanding the origins and consequences of substance use disorders (SUDs). Specifically, we hypothesize that inherited vulnerability in two systems, disinhibition and negative affect, interacts with adolescent and early-adult experience and life circumstance to affect the likelihood of SUDs in adulthood. Through use of overlapping cohorts, we will chart the development of SUDs from pre-adolescence through early adulthood. The younger cohort, originally assessed at age 11, will be followed through age 24-25; the older cohort, originally assessed at age 17, will be followed through age 29-30. Participants complete a comprehensive in-person assessment that includes clinical interviews, psychophysiological indicators of risk, and self-reports of personality and environmental risk. DNA samples will also be obtained to enable future molecular genetic investigation. Analysis of data from early waves has allowed us to characterize a disinhibitory pathway that: 1) begins in pre-adolescence with early manifestations of problem behavior, 2) is predictive of SUD risk, 3) underlies the comorbidity of a wide range of disruptive disorders, 4) is substantially heritable, and 5) is indexed by psychophysiological markers of risk, like P3. Although the effects are not as marked, we have also shown that negative emotionality and internalizing disorders are associated with and prospectively predict the onset of SUDs in adulthood. Analysis of data from the proposed adult assessments will allow us to investigate the impact of these two pathways on the persistence and desistence of substance use and abuse at these life stages.